ENST00000482318.5:n.*1077C>G

Variant names:

• chr21-34792091-G-C
• rs535532916
• ENST00000482318.5:n.*1077C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP2 BA1

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.*44C>G is a 3' UTR variant. MAF of 0.01 (1.31%, 885/67420 alleles) in the European (non-Finnish) subpopulation of the gnomAD v3.1.2 cohort is ≥ 0.0015 (0.15%) (BA1). This variant is reported in 4 homozygotes in gnomAD v3.1.2 (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2 LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014163/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.0085 (4 hom., cov: 32)
  • Exomes 𝑓: 0.012 (110 hom.)
• Consequence: RUNX1 ENST00000482318.5 non_coding_transcript_exon
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: -0.209
• Publications: 0 publications found

Genes affected

RUNX1 (HGNC:10471): (RUNX family transcription factor 1) Core binding factor (CBF) is a heterodimeric transcription factor that binds to the core element of many enhancers and promoters. The protein encoded by this gene represents the alpha subunit of CBF and is thought to be involved in the development of normal hematopoiesis. Chromosomal translocations involving this gene are well-documented and have been associated with several types of leukemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

RUNX1 Gene-Disease associations (from GenCC):

• hereditary thrombocytopenia and hematologic cancer predisposition syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000482318.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.*44C>G		3_prime_UTR	Exon 9 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.*44C>G		3_prime_UTR	Exon 6 of 6	NP_001001890.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000482318.5	TSL:1	n.*1077C>G		non_coding_transcript_exon	Exon 7 of 7	ENSP00000477067.1
	RUNX1	ENST00000675419.1	MANE Select	c.*44C>G		3_prime_UTR	Exon 9 of 9	ENSP00000501943.1
	RUNX1	ENST00000300305.7	TSL:1	c.*44C>G		3_prime_UTR	Exon 8 of 8	ENSP00000300305.3

Frequencies

GnomAD3 genomes AF: 0.00852 AC: 1281 AN: 150344 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00240

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00624

Gnomad ASJ AF: 0.0320

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0131

Gnomad OTH AF: 0.00725

GnomAD2 exomes AF: 0.0109 AC: 59 AN: 5428 AF XY: 0.0112

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00500

Gnomad ASJ exome AF: 0.0348

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00987

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.00658

GnomAD4 exome AF: 0.0124 AC: 13700 AN: 1104612 Hom.: 110 Cov.: 17 AF XY: 0.0123 AC XY: 6571 AN XY: 536204

African (AFR) AF: 0.00159 AC: 34 AN: 21372

American (AMR) AF: 0.00328 AC: 29 AN: 8840

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 505 AN: 14836

East Asian (EAS) AF: 0.00 AC: 0 AN: 25150

South Asian (SAS) AF: 0.00529 AC: 236 AN: 44600

European-Finnish (FIN) AF: 0.00665 AC: 181 AN: 27238

Middle Eastern (MID) AF: 0.00652 AC: 20 AN: 3068

European-Non Finnish (NFE) AF: 0.0133 AC: 12194 AN: 914626

Other (OTH) AF: 0.0112 AC: 501 AN: 44882

GnomAD4 genome AF: 0.00852 AC: 1282 AN: 150452 Hom.: 4 Cov.: 32 AF XY: 0.00834 AC XY: 613 AN XY: 73504

African (AFR) AF: 0.00239 AC: 99 AN: 41374

American (AMR) AF: 0.00623 AC: 94 AN: 15096

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 111 AN: 3464

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5108

South Asian (SAS) AF: 0.00455 AC: 22 AN: 4830

European-Finnish (FIN) AF: 0.00395 AC: 39 AN: 9876

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0131 AC: 885 AN: 67410

Other (OTH) AF: 0.00717 AC: 15 AN: 2092

Alfa AF: 0.0106 Hom.: 2

Bravo AF: 0.00836

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Jul 20, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Benign:1

Jun 30, 2022

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

NM_001754.5(RUNX1):c.*44C>G is a 3' UTR variant. MAF of 0.01 (1.31%, 885/67420 alleles) in the European (non-Finnish) subpopulation of the gnomAD v3.1.2 cohort is ≥ 0.0015 (0.15%) (BA1). This variant is reported in 4 homozygotes in gnomAD v3.1.2 (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.3
DANN	Benign	0.72
PhyloP100		-0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs535532916; hg19: chr21-36164388;